Pituitary tumors contain a side population with tumor stem cell-associated characteristics

Abstract

Pituitary adenomas cause significant endocrine and mass-related morbidity. Little is known about the mechanisms that underlie pituitary tumor pathogenesis. In the present study, we searched for a side population (SP) in pituitary tumors representing cells with high efflux capacity and potentially enriched for tumor stem cells (TSCs). Human pituitary adenomas contain a SP irrespective of hormonal phenotype. This adenoma SP, as well as the purified SP (pSP) that is depleted from endothelial and immune cells, is enriched for cells that express 'tumor stemness' markers and signaling pathways, including epithelial-mesenchymal transition (EMT)-linked factors. Pituitary adenomas were found to contain self-renewing sphere-forming cells, considered to be a property of TSCs. These sphere-initiating cells were recovered in the pSP. Because benign pituitary adenomas do not grow in vitro and have failed to expand in immunodeficient mice, the pituitary tumor cell line AtT20 was further used. We identified a SP in this cell line and found it to be more tumorigenic than the non-SP 'main population'. Of the two EMT regulatory pathways tested, the inhibition of chemokine (C-X-C motif) receptor 4 (CXCR4) signaling reduced EMT-associated cell motility in vitro as well as xenograft tumor growth, whereas the activation of TGFb had no effect. The human adenoma pSP also showed upregulated expression of the pituitary stem cell marker SOX2. Pituitaries from dopamine receptor D2 knockout (Drd2 K/K ) mice that bear prolactinomas contain more pSP, Sox2C , and colony-forming cells than WT glands. In conclusion, we detected a SP in pituitary tumors and identified TSC-associated characteristics. The present

Differential Expression of Stem Cell Markers in Human Adamantinomatous Craniopharyngioma and Pituitary Adenoma

“…The same mechanism has also been suggested to give rise to tumours characterized by uncontrolled cell division. Notably, previous studies have demonstrated the presence of stem cells through SOX2 and SOX9 expression in pituitary adenoma and ACP [5,6,17,23]. …”

“…They have been demonstrated to form pituitary spheres and to secrete hormones in culture [5,6]. Pituitary adenomas are benign tumours, but their hormone production and associated growth disorders are related to increased morbidity [7].…”

Basic Research Advances on Pituitary Stem Cell Function and Regulation

“…This indirect paracrine function of stem cells is of relevance to human pituitary tumour formation, as this mouse model recapitulates the most common paediatric pituitary tumour, adamantinomatous craniopharyngioma, also harbouring mutations in CTNNB1 activating the WNT signalling pathway. There is evidence of cells isolated from pituitary adenomas with similarities in their in vitro capacity and gene expression to pituitary stem cells [46]. These are also defined by a side population efflux profile upon flow cytometry following Hoechst dye labelling, which can be enriched for stem cells in many tissue types, including the pituitary [47].…”

Expression of Stem Cell Markers and Dopamine D2 Receptors in Human and Rat Prolactinomas

“…Pituitary adenoma stem-like cells were first isolated from a case of human nonfunctional adenoma and another case of human somatotrophic adenoma, respectively, by Xu [20]. Their existence was established in several recent studies [21–23]. Stem cell markers are widely used for the identification of TSLCs.…”